Molecular Genetics of Deafness: The Roles of MYO15 and Thyroid Hormone.

Deafness;Inner Ear;MYO15;Thyroid Hormone;Genetics;Health Sciences;Human Genetics

Fang, QingMeisler, Miriam H. ;

University of Michigan

关键词: Deafness;    Inner Ear;    MYO15;    Thyroid Hormone;    Genetics;    Health Sciences;    Human Genetics;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/78810/qingf_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Deafness affects about 250 million people, and genetics contributes to approximately half of the cases.Environmental influences include exposure to noise, ototoxic drugs, physical trauma, and systemic diseases, such as hypothyroidism.This thesis presents functional analysis of a Mendelian cause of human deafness, mutations in the unconventional myosin MYO15, and a genetically complex disorder, susceptibility to hearing impairment due to hypothyroidism.Mutations in the motor or tail domain of MYO15 cause congenital deafness and vestibular dysfunction.These domains are required for stereocilia elongation and WHIRLIN transport.Some isoforms of MYO15 contain a proline-rich region of unknown function.We generated a mouse model of a human mutation that eliminates these isoforms.These mutants have profound deafness but lack severe vestibular abnormalities, and have unique cochlear stereocilia pathology.Initial elongation occurs but is not maintained, implicating the proline-rich region in hair bundle preservation.There is no evidence of allelic complementation for hearing or hair bundle maintenance in compound heterozygotes with different combinations of mutant alleles, proving functional importance of the full length MYO15 isoform.Thyroid hormone (TH) has pleiotropic effects on cochlear development, and genomic variation influences the severity of the hearing problem.Prop1df and Pou1f1dw mutant mice lack pituitary thyrotropin, which causes severe TH deficiency and variable hearing impairments.DW-Pou1f1dw mutants have multiple cochlear abnormalities and are profoundly deaf.In contrast, DF-Prop1df mutants have mild hearing impairment and few permanent abnormalities.Transfer of these embryos to surrogates demonstrated that their susceptibility to hearing impairment is intrinsic to the fetus.A genome scan conducted on hearing progeny of an F1 intercross between DW-Pou1f1dw carriers and Mus castaneus identified a single locus on chromosome 2, modifier of dw hearing, Mdwh, that rescues hearing despite persistent hypothyroidism.A known modifier in this region is neither necessary nor sufficient to rescue DW hearing, suggesting that Mdwh is a novel protective locus.Microarray analysis identified cochlear gene expression changes caused by hypothyroidism in Pou1f1dw mice that are positional candidates for the modifier gene.Identification of the protective modifier will enhance our understanding of the mechanisms of hypothyroidism-induced hearing impairment and may lead to rational therapeutics.